Principles of Differentiation and Prescription for Vitiligo in Traditional Chinese Medicine Based on a Literature Investigation

Received: May 13, 2015 Accepted after revision: October 19, 2015 Published online: December 3, 2015 2015 The Author(s) Published by S. Karger AG, Basel 2296 7362/15/0024 0149$39.50/0 This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/services/openaccesslicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Original Paper Principles of Differentiation and Prescription for Vitiligo in Traditional Chinese Medicine Based on a Literature Investigation Chunjie Gao Lili Yang Mengjiao Chen Huimin Zhang Department of Dermatology, Shu-guang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China Key Words Principles of differentiation Prescription Traditional Chinese medicine Vitiligo Literature investigation Logistic multiple regression Abstract Background/Aims: Vitiligo is a common disorder of depigmented skin. Traditional Chinese medicine (TCM) has been proved to be effective for the treatment of vitiligo, but the standard differential syndromes and effective formulas and herbs are still controversial. The aim of this study is to analyze the principles of differentiation and prescription in treating vitiligo in TCM based on a large-scale literature investigation. Methods: Articles about vitiligo treatment using TCM were searched in three databases, including China National Knowledge Infrastructure (1979 2014), China Science Periodical Database (1990 2014) and PubMed (1984 2014). The frequency of differential syndromes, formulas and herbs was analyzed using a metrological method and logistic multiple regression analysis. Results: Five syndromes account for the major differential categories in vitiligo: liver and kidney deficiency, Qi stagnation and blood stasis, liver depression and Qi stagnation, disharmony between Qi and blood, and blood conflicting with wind. The common formula prescriptions most frequently used were Tong-Qiao-Huo- Xue decoction, Xiao-Yao powder and Si-Wu decoction. The most frequently prescribed herbs were Angelica sinensis, Ligusticum wallichii,, Polygonum multiflorum, Fructus psoraleae, Radix Paeoniae Rubra, Rehmannia glutinosa, Glossy Privet Fruit, Eclipta alba, Salvia miltiorrhiza, Liquorice, and Angelica dahurica, which shows that the treatment principles of vitiligo are tonifying the liver and kidney, activating blood and expelling wind. Conclusion: The most frequent syndromes of vitiligo are liver and kidney deficiency, Qi stagnation and blood stasis. Most TCM doctors prefer prescribing herbs with efficacy in tonifying the liver and kidney, activating blood and expelling wind in treating vitiligo. 2015 The Author(s) Published by S. Karger AG, Basel Chunjie Gao and Lili Yang contributed equally to this article and should be considered as first authors. Huimin Zhang Department of Dermatology, Shu-guang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine 185 Pu an Road, Shanghai 200021 (China) E-Mail happy2003_1 @ msn.com

150 Introduction Vitiligo is a disorder of pigmentation characterized by the presence of depigmented skin macules due to the chronic and progressive loss of melanocytes from the cutaneous epidermis [1]. Vitiligo affects approximately 0.5 1% of the world s population [1]. People with this disorder can experience emotional stress, particularly if vitiligo develops on visible areas of the body [2]. The cause of vitiligo remains unknown, and the treatment also remains difficult [3]. A number of therapies, including corticosteroids, topical immunomodulators, photo(chemo)therapy and surgery, have proven to be partially successful but show various side effects [4]. Traditional Chinese medicine (TCM), the most common complementary and alternative medicine, has been widely used over 1,000 years in China. There are three Chinese medical terms whose descriptions match vitiligo, namely Bai-Dian, Bai-Bo-Feng or Ban-Bo [5]. TCM could be effective in stopping progression of the disease and achieving repigmentation, which has been a popular treatment for vitiligo in China [6]. However, with different classifications of the etiology and pathogenesis of vitiligo, generations of TCM physicians have prescribed various herbal formulas with distinct differential syndromes [7]. A large-scale literature investigation regarding the widely accepted differentiation of and effective formulas and herbs for vitiligo is still lacking [8]. The aim of this study is to analyze the principles of TCM differentiation and prescription for treating vitiligo based on a large-scale literature investigation, using a metrological method and logistic multiple regression analysis. Our data could provide useful information about vitiligo treatment in TCM. Materials and Methods Data Resources and Study Sample A literature search was conducted to record TCM differentiations, formulas and herbs prescribed for treating vitiligo in databases, including China National Knowledge Infrastructure (1979 2014), China Science Periodical Database (1990 2014) and PubMed (1984 2014). The following keywords and subject terms were searched: traditional Chinese medicine and vitiligo, or Chinese herbs and vitiligo. Two authors independently assessed study eligibility and methodological quality and extracted data. The final decision on unclear criteria in the literature was made by the two authors after thorough discussion. Studies were included or excluded in the analysis depending on the following standards. Inclusion Criteria Studies were included in the analysis if they (1) were clinical randomized controlled studies, clinical reports, case reports or medication experience of renowned TCM doctors; (2) had clear diagnoses complying with diagnostic criteria of vitiligo, and (3) contained specific syndrome classifications or descriptions. Exclusion Criteria We excluded the following: (1) studies focusing on an adverse reaction or toxic effect of TCM herbs; (2) studies in which TCM herbs acted as adjuvant therapy for vitiligo; (3) studies in which TCM herbs were among various remedies and could not be confirmed as the main effective medication; (4) studies on patients without vitiligo, or if the outcome indicator did not comply with the inclusion criteria; (5) studies containing apparent errors or overlapping data; (6) studies based on animal experiments, and (7) reviews of literature.

151 Table 1. The 9 most frequently prescribed herbal formulas for treating vitiligo Order Herbal formulas Syndromes liver and kidney deficiency Qi stagnation and blood stasis liver depression and Qi stagnation disharmony between Qi and blood blood conflicting with wind Total frequency (n = 112) 1 Tong-Qiao-Huo-Xue decoction 1 6 0 0 0 7 2 Xiao-Yao powder 0 1 4 0 0 5 3 Si-Wu decoction 2 1 1 0 1 5 4 Chai-Hu-Shu-Gan powder 0 1 3 0 0 4 5 Liu-Wei-Di-Huang pill 4 0 0 0 0 4 6 Ba-Zhen decoction 0 0 0 3 0 3 7 Er-Zhi pill 2 0 0 0 0 2 8 Bai-Bo decoction 1 0 0 1 0 2 9 Wu-Zi-Yan-Zong pills 2 0 0 0 0 2 Statistical Analysis A statistical analysis of the frequency of syndromes and herbal formulas for the treatment of vitiligo was conducted using binary logistic stepwise regression. Patterns were set as the dependent variable, and herbs were the independent variable. For analyzing one typical pattern, the target pattern was set as 1 and the other ones were set as 0. In the analysis of each herb, the prescribed herb was set as 1, and herbs not appearing in the formulas were set as 0. By the likelihood ratio, score and Wald tests, the pattern-herb model was established (p < 0.001). Statistical significance was considered at p < 0.05 for each pattern-herb regression equation. All data were stored and analyzed using SPSS software (version 21.0 for Windows). The names of Chinese herbs in the literature were standardized according to the 2010 Chinese Pharmacopoeia [9]. Results The Syndromes of Vitiligo Of the 218 records initially identified from three databases after removing duplicates, 134 studies were discarded because, after reviewing the titles and abstracts, it was clear that these articles did not meet the inclusion criteria. A total of 84 studies were assessed in full text for eligibility, of which 6 were excluded for the following reasons: duplicated data (n = 2), review articles (n = 2) and insufficient information (n = 2). Finally, 78 articles including 163 formulas with 15 syndrome types of TCM were available for analysis. Among the 15 syndrome types of TCM in vitiligo, 5 syndromes accounted for the major differential categories. The syndrome of liver and kidney deficiency was the most frequent differentiation pattern, with 49 formulas accounting for 30.06%, followed by the syndrome of Qi stagnation and blood stasis with 26 formulas accounting for 15.95%. The syndrome of liver depression and Qi stagnation with 17 formulas accounted for 10.43%. Eleven formulas were proscribed for the syndrome of disharmony between Qi and blood, which accounted for 6.75%. Finally, the syndrome of blood conflicting with wind with 9 formulas accounted for 5.52%. The Herbal Formulas for Treating Vitiligo The 3 most frequently prescribed herbal formulas for treating vitiligo among the 163 formulas were Tong-Qiao-Huo-Xue decoction, Xiao-Yao powder and Si-Wu decoction. The 9 most commonly used herbal formulas among 112 formulas in the 5 syndromes for vitiligo are illustrated in table 1.

152 Table 2. The 12 most frequently prescribed Chinese herbs for treating vitiligo Chinese herb Appearance, n Frequency, % Angelica sinensis (Dang-gui) 74 66.07 Ligusticum wallichii (Chuan-xiong) 63 56.25 (Ji-li) 52 46.43 Polygonum multiflorum (He-shou-wu) 51 45.54 Fructus psoraleae (Bu-gu-zhi) 49 43.75 Radix Paeoniae Rubra (Chi-shao) 47 41.96 Rehmannia glutinosa (Shu-di-huang) 42 37.5 Glossy Privet Fruit (Nv-zhen-zi) 39 34.8 Eclipta alba (Han-lian-cao) 38 33.9 Salvia miltiorrhiza (Dan-shen) 37 33.0 Liquorice (Gan-cao) 36 32.1 Angelica dahurica (Bai-zhi) 33 29.5 The Herbs Prescribed for Treating Vitiligo The 12 most frequently prescribed Chinese herbs for vitiligo are summarized in table 2. These herbs are Angelica sinensis ( Dang-gui in Chinese), Ligusticum wallichii (Chuan-xiong), (Ji-li), Polygonum multiflorum (He-shou-wu), Fructus psoraleae (Bu-gu-zhi), Radix Paeoniae Rubra (Chi-shao), Rehmannia glutinosa (Shu-di-huang), Glossy Privet Fruit (Nv-zhen-zi), Eclipta alba (Han-lian-cao), Salvia miltiorrhiza (Dan-shen), Liquorice (Gan-cao) and Angelica dahurica (Bai-zhi). The frequencies of Chinese herbs prescribed for vitiligo in the 5 most common patterns are illustrated in table 3. Differences in Herbs Prescribed for Syndromes Analyzed by Multiple Logistic Regressions To analyze specifically prescribed herbs for each syndrome, multiple logistic regression analysis was used. In the following, logistic regression equations of herbs are shown for each syndrome, and the statistical data are illustrated in tables 4 8. Syndrome of Liver and Kidney Deficiency logit(p) = 1.288 to 1.466 A. (Dang-gui) + 1.735 P. multiflorum (He-shou-wu) + 1.769 F. psoraleae (Bu-gu-zhi) + 1.612 R. glutinosa (Shu-di-huang) + 1.775 Glossy Privet Fruit (Nvzhen-zi) 1.911 Carthamus tinctorius (Hong-hua) 1.632 Bupleurum chinense (Chai-hu). Syndrome of Qi Stagnation and Blood Stasis logit(p) = 2.478 to 5.409 T. terrestris (Ji-li) + 3.33 Radix Paeoniae Rubra (Chi-shao) + 3.378 A. dahurica (Bai-zhi) + 4.331 C. tinctorius (Hong-hua) 5.978 Radix Saposhnikoviae (Fang-feng) 23.101 Rhizoma Atractylodis Macrocephalae (Bai-zhu) 21.468 Codonopsis pilosula (Dang-shen). Syndrome of Liver Depression and Qi Stagnation logit(p) = 6.071 to 3.468 R. glutinosa (Shu-di-huang) 5.931 A. dahurica (Bai-zhi) + 4.448 B. chinense (Chai-hu) + 3.754 Paeonia lactiflora (Bai-shao) + 4.859 Radix Curcumae (Yu-jin). Syndrome of Disharmony between Qi and Blood logit(p) = 3.123 to 20.825 Barbary Wolfberry Fruit (Gou-qi-zi) + 1.809 Caulis Spatholobi (Ji-xue-teng) + 4.093 C. pilosula (Dang-shen). Syndrome of Blood Conflicting with Wind logit(p) = 4.566 + 1.925 Radix Rehmanniae (Sheng-di-huang) + 3.812 Herba Schizonepetae (Jin-jie) + 3.086 Cortex Dictamni (Bai-xian-pi).

153 Table 3. Frequencies of Chinese herbs prescribed for vitiligo in 5 patterns Order Syndromes Liver and kidney deficiency 1 Polygonum multiflorum 33 (67.35) 2 Glossy Privet Fruit 32 (65.31) 3 Fructus psoraleae 32 (65.31) 4 Eclipta alba 29 (59.18) 5 Rehmannia glutinosa 28 (57.14) 6 Angelica sinensis 26 (53.06) 7 25 (51.02) 8 Semen Cuscutae 20 (40.82) 9 Ligusticum wallichii 19 (38.78) 10 Barbary Wolfberry Fruit 19 (38.78) 11 Liquorice 18 (36.73) 12 Radix Astragali 16 (32.65) Qi stagnation and blood stasis Radix Paeoniae Rubra 20 (76.92) Ligusticum wallichii 19 (73.08) Carthamus tinctorius 17 (65.38) Angelica sinensis 17 (65.38) Semen Persicae 15 (57.69) Angelica dahurica 14 (53.85) Salvia miltiorrhiza 12 (46.15) Psoralea corylifolia 10 (38.46) Glycyrrhizae 8 (30.77) Bupleurum chinense 7 (26.92) 7 (26.92) Fallopia multiflora 7 (26.92) Liver depression and Qi stagnation Angelica sinensis 15 (88.24) Bupleurum chinense 15 (88.24) Radix Curcumae 13 (76.47) 11 (64.71) Paeonia lactiflora 11 (64.71) Ligusticum wallichii 10 (58.82) Rhizoma cyperi 7 (41.18) Poria cocos 7 (41.18) Salvia miltiorrhiza 5 (29.41) Radix Paeoniae Rubra 5 (29.41) Rehmannia glutinosa 5 (29.41) Carthamus tinctorius 5 (29.41) Disharmony between Qi and blood Angelica sinensis 9 (81.82) Ligusticum wallichii 8 (72.73) Fallopia multiflora 6 (54.55) Caulis Spatholobi 6 (54.55) Rhizoma Atractylodis Macrocephalae 6 (54.55) Astragalus membranaceus 5 (45.45) Codonopsis pilosula 5 (45.45) Paeonia lactiflora Glycyrrhizae Radix Saposhnikoviae Radix Paeoniae Rubra Blood conflicting with wind Radix Rehmanniae 7 (77.78) Angelica sinensis 7 (77.78) Ligusticum wallichii 7 (77.78) Radix Saposhnikoviae 6 (66.67) Radix Paeoniae Rubra 6 (66.67) 5 (55.56) 5 (55.56) Cortex Dictamni Bupleurum chinense Salvia miltiorrhiza Periostracum cicada Lemna minor Values are expressed as frequencies with percentages in parentheses. Table 4. Syndrome of liver and kidney deficiency Angelica sinensis (Dang-gui) 1.466 0.683 4.614 0.032 0.231 Polygonum multiflorum (He-shou-wu) 1.735 0.654 7.027 0.008 5.668 Fructus psoraleae (Bu-gu-zhi) 1.769 0.693 6.518 0.011 5.866 Rehmannia glutinosa (Shu-di-huang) 1.612 0.678 5.652 0.017 5.013 Glossy Privet Fruit (Nv-zhen-zi) 1.775 0.611 8.447 0.004 5.900 Carthamus tinctorius (Hong-hua) 1.911 0.763 6.283 0.012 0.148 Bupleurum chinense (Chai-hu) 1.632 0.763 4.579 0.032 0.195

154 Table 5. Syndrome of Qi stagnation and blood stasis (Ji-li) 5.409 1.653 10.709 0.001 0.004 Radix Paeoniae Rubra (Chi-shao) 3.330 0.986 11.416 0.001 27.935 Angelica dahurica (Bai-zhi) 3.378 1.161 8.464 0.004 29.326 Carthamus tinctorius (Hong-hua) 4.331 1.406 9.493 0.002 76.056 Radix Saposhnikoviae (Fang-feng) 5.978 2.019 8.769 0.003 0.003 Rhizoma Atractylodis Macrocephalae (Bai-zhu) 23.101 7,774.266 0.000 0.998 0.000 Codonopsis pilosula (Dang-shen) 21.468 9,390.897 0.000 0.998 0.000 Table 6. Syndrome of liver depression and Qi stagnation Rehmannia glutinosa (Shu-di-huang) 3.468 1.813 3.660 0.056 0.031 Angelica dahurica (Bai-zhi) 5.931 2.337 6.439 0.011 0.003 Bupleurum chinense (Chai-hu) 4.448 1.587 7.852 0.005 85.474 Paeonia lactiflora (Bai-shao) 3.754 1.423 6.964 0.008 42.689 Radix Curcumae (Yu-jin) 4.859 1.677 8.397 0.004 128.900 Table 7. Syndrome of disharmony between Qi and blood Barbary Wolfberry Fruit (Gou-qi-zi) 20.825 6,942.424 0.000 0.998 0.000 Caulis Spatholobi (Ji-xue-teng) 1.809 0.836 4.676 0.031 6.102 Codonopsis pilosula (Dang-shen) 4.093 1.245 10.802 0.001 59.946 Table 8. Syndrome of blood conflicting with wind Radix Rehmanniae (Sheng-di-huang) 1.925 1.033 3.476 0.062 6.856 Herba Schizonepetae (Jin-jie) 3.812 1.110 11.790 0.001 45.256 Cortex Dictamni (Bai-xian-pi) 3.086 1.313 5.522 0.019 21.887 According to the regression equation of the classification of medication, P. multiflorum (He-shou-wu), F. psoraleae (Bu-gu-zhi), R. glutinosa (Shu-di-huang) and Glossy Privet Fruit (Nv-zhen-zi) were specifically used for the deficiency of liver and kidney syndrome of vitiligo. Radix Paeoniae Rubra (Chi-shao), C. tinctorius (Hong-hua) and A. dahurica (Bai-zhi) were typically prescribed for Qi stagnation and blood stasis. Radix Curcumae (Yu-jin), Radix Bupleuri (Chai-hu) and Radix Paeoniae Alba (Bai-shao) were often used for the syndrome of liver depression and Qi stagnation. C. pilosula (Dang-shen) and Caulis Spatholobi (Ji-xue-teng) were used for the deficiency of Qi and blood. Radix Rehmanniae (Sheng-di-huang), Herba Schizonepetae (Jin-jie) and Cortex Dictamni (Bai-xian-pi) were most likely to be used for treating patients with the syndrome of blood conflicting with wind.

155 Discussion Vitiligo is a relatively common dermatologic finding which has been observed since ancient times [10]. TCM herbs have been used as effective anti-vitiligo agents for over 1,000 years in China [11]. However, the published literature on the differentiation of vitiligo and herbal formulas for its treatment is controversial and inconclusive [12]. To analyze standard differentiation of and effective formulas and Chinese herbs for vitiligo, we performed a largescale literature investigation regarding the differentiation of syndromes and herbal formulas for vitiligo. According to our statistical data, 5 syndromes account for the major differential categories among a total of 15 syndromes in vitiligo. They are the syndrome of liver and kidney deficiency, Qi stagnation and blood stasis, liver depression and Qi stagnation, disharmony between Qi and blood, and blood conflicting with wind. The 12 most frequently prescribed Chinese herbs for vitiligo are A. sinensis (Dang-gui), L. wallichii (Chuan-xiong), T. terrestris (Ji-li), P. multiflorum (He-shou-wu), F. psoraleae (Bu-gu-zhi), Radix Paeoniae Rubra (Chi-shao), R. glutinosa (Shu-di-huang), Glossy Privet Fruit (Nv-zhen-zi), E. alba (Han-lian-cao), S. miltiorrhiza (Dan-shen), Liquorice (Gan-cao) and A. dahurica (Bai-zhi). Most of these frequently used herbs have functions of nourishing the liver and kidney, dispelling wind and activating blood. Based on an analysis of herb frequency, we found that Chinese herbs with the function of nourishing the liver and kidney appear in every syndrome of vitiligo, which suggests that the key treatment principle for vitiligo is nourishing the liver and kidney. Moreover, our data shows that A. dahurica (Bai-zhi) and T. terrestris (Ji-li), two herbs with the function of expelling wind, are most commonly prescribed by TCM doctors. This could be explained by the ancient classification of the pathogenesis of vitiligo in TCM, which was ascribed to wind evil [13]. Ancient TCM doctors called vitiligo Bai-Bo-Feng, Feng meaning wind, which indicates that wind evil is thought to play an important role in the development of vitiligo [14]. Chinese herbs with efficacy of dispelling the wind, therefore, are frequently used in TCM formulas for vitiligo [13]. In TCM, interestingly, physicians often prescribe black or dark herbs in treating disorders with white or pale symptoms [15]. White or pale symptoms are thought to be caused by deficiency of Qi or kidney; yet, black herbs nourish the kidney, which is the theory of the herb color-effect phenomenon in TCM [16]. Vitiligo, which is characterized by depigmented white macules in the skin, therefore, is often treated with black herbal medication. Our data show that many of the most frequently prescribed herbs are black, including P. multiflorum (Heshou-wu), R. glutinosa (Shu-di-huang), F. psoraleae (Bu-gu-zhi), Glossy Privet Fruit (Nv-zhenzi) and S. miltiorrhiza (Dan-shen). These herbal medications are effective in nourishing the kidney, complying with the treatment principles of vitiligo. References 1 Taieb A, Picardo M; VETF Members: The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res 2007; 20: 27 35. 2 Kent G, Al Abadie M: Psychologic effects of vitiligo: a critical incident analysis. J Am Acad Dermatol 1996; 35: 895 898. 3 Daniel BS, Wittal R: Vitiligo treatment update. Australas J Dermatol 2015; 56: 85-89. 4 Abu Tahir M, Pramod K, Ansari SH, Ali J: Current remedies for vitiligo. Autoimmun Rev 2010; 9: 516 520. 5 Chen HY, Xu AE: Treatment of vitiligo in traditional Chinese medicine from Sui Dynasty to Qing Dynasty. Chin J Dermatovenerol Integr Trad West Med 2006; 5: 57 59. 6 Ghafourian E, Ghafourian S, Sadeghifard N, Mohebi R, Shokoohini Y, Nezamoleslami S, Hamat RA: Vitiligo: symptoms, pathogenesis and treatment. Int J Immunopathol Pharmacol 2014; 27: 485 489.

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